The present invention relates to novel benzimidazole derivatives, pharmaceutical compositions containing these compounds, and methods of treatment therewith.
The compounds of the invention are useful in the treatment of central nervous system diseases and disorders, which are responsive to modulation of the GABAA receptor complex, and in particular for inducing and maintaining anaesthesia, sedation and muscle relaxation, as well as for combating febrile convulsions in children.
The compounds of the invention may also be used by veterinarians.
Agents that bind or interact with the modulatory sites on the GABAA receptor complex, such as for example the benzodiazepine receptor, can have either enhancing effect on the action of GABA, i.e. a positive modulatory effect of the receptor (agonists, partial agonists), an attenuating effect on the action of GABA, i.e. negative modulation of the receptor (inverse agonists, partial inverse agonists), or they can block the effect of both agonists and inverse agonists (antagonists or ligands without intrinsic activity).
Agonists generally produce muscle relaxant, hypnotic, sedative, anxiolytic, and/or anticonvulsant effects, while inverse agonists produce pro-convulsive, anti-inebriant or anxiogenic effects. Compounds with anxiolytic effects, but with or without reduced muscle relaxant, hypnotic and sedative effects, are characterised as partial agonists. Partial inverse agonists are considered to be useful as cognition enhancers.
Full agonists of the benzodiazepine receptor are considered useful as anaesthetics. However, many drugs presently available as anaesthetics, and especially pre-anaesthetics, give rise to hang-over effects as well as long awakening times, wherein careful monitoring of the patient is necessary. Anaesthetics with a long half-life may also impose difficulties during incidents of overdosing i.e. prolonged respiratory depression. Furthermore, some currently used drugs cannot be used for anaesthetising children as deaths have been reported in children after prolonged use of Propofol. Some anaesthetics are gasses which inherently possesses a contamination problem for the medical staff.
A well known anaesthetic, Propofol, is administered as a mixture of soybean oil, glycerol and purified egg phosphatide, which mixture nourish bacterial growth. Administration of bacterially contaminated Propofol has been reported to cause sepsis and death [Wiklund et al.; The New England Journal of Medicine 1997 337 (16) 1132-1141]. Further, compounds with a long in vivo half-life will give problems with accumulation during and after prolonged treatment e.g. when administered to patients constrained to a respirator. Short half-lives wherein the compounds are metabolised to inactive metabolites allow for a predictable correlation of dose and duration of pharmacological effect.
Ideally the anaesthestising effect should be observed shortly after a bolus injection or infusion of the compound. A rapid onset of action minimises the period of anxiety and uneasiness experienced by patients going into surgery.
Patients suffering from severe and continuous epileptic attacks presently treated with large amounts of sedatives, e.g. benzodiazepines, will benefit from shorter acting compounds with no hang-over or long lasting sedating effect.
As the preferred route of administration is by intravenous injection or infusion, the anaesthestising compounds should preferably be water soluble.
EP 616807 describes benzimidazole compounds for use as benzodiazepine receptor ligands.
WO 96133194, WO 96133191 and WO 96/33192 describe benzimidazole compounds having affinity for the GABA receptor complex.
WO 98134923 describes phenylbenzimidazole derivatives as ligands for the GABA receptor complex.
WO 98/17651 describes benzimidazole compounds for use as e.g. anaesthetics. However, the presently disclosed compounds are superior to the compounds previously described.
It is an object of the invention to provide novel compounds useful as anaesthetics and/or pre-anaesthetics, sedatives, muscle relaxants, and for the treatment of febrile convulsions in children, status epilepticus, for use to patients constrained to a respirator as well as for veterinarian uses.
In its first aspect, the invention provides a benzimidazole derivative represented by the general Formula I, 
or a pharmaceutically acceptable salt thereof,
wherein,
Rxe2x80x2 represents a group of the formula -(alk)q-Rxe2x80x2,
wherein
(alk) represents alkyl, alkenyl or alkynyl,
q is 0 or 1,
R1 represents a group of the formula xe2x80x94CO2R2, wherein
R2 represents hydrogen, alkyl, hydroxy-alkyl, alkoxy-alkyl, thioalkoxy-alkyl, alkyl-xe2x80x9cHeterocyclexe2x80x9d, or -alkyl-NR3R4,
wherein
xe2x80x9cHeterocyclexe2x80x9d represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl, and a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-xe2x80x9cHeterocyclexe2x80x9d, -(alkyl)p-CO2-xe2x80x9cHeterocyclexe2x80x9d or -(alkyl-CO2)s-(alkyl)t-COR5,
in which formulas
p, s and t independently of each another is 0 or 1,
xe2x80x9cHeterocyclexe2x80x9d represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl,
R5 represents hydroxy, alkoxy, hydroxy-alkoxy, alkoxyxe2x80x94alkoxy, thioalkoxy-alkoxy, or a group of the formula xe2x80x94NR6R7 or xe2x80x94O-alkyl-NR6R7,
in which formulas
R6 and R7 independently of each another represent hydrogen, alkyl, cycloalkyl or a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl, or
R6 and R7 together with the nitrogen to which they are attached form a mono- or polycyclic heterocyclic group, which heterocyclic group may be substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl; and
R3 and R4 independently of each another represent hydrogen, alkyl or cycloalkyl, or
R3 and R4 together with the nitrogen to which they are attached form a mono- or poly-cyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyt; or
R1 represents a group of the formula 
X represents N or CH,
R12 represents hydrogen, alkyl alkoxy or hydroxy-alkyl, and
R13 represents hydrogen, hydroxy, alkyl, alkoxy or hydroxy-alkyl; or
R1 represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of alkyl, hydroxy-alkyl, alkoxy-alkyl, carboxyl, and acyl, and a group of the formula -(alkyl)p-aryl, -(alkyl)p-xe2x80x9cHeterocyclexe2x80x9d, -(alkyl)p-CN or -(alkyl-CO2)s-(alkyl)t-COR5,
in which formulas
p, s and t independently of each another is 0 or 1,
xe2x80x9cHeterocyclexe2x80x9d represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl,
R5 represents hydroxy, alkoxy, hydroxy-alkoxy, alkoxyxe2x80x94alkoxy, thioalkoxy-alkoxy, or a group of the formula xe2x80x94NR6R7 or xe2x80x94O-alkyl-NR6R7,
in which formulas
R6 and R7 independently of each another represent hydrogen, alkyl, cycloalkyl or a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl, or
R6 and R7 together with the nitrogen to which they are attached form a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl; and
Rxe2x80x3 represents -(alkyl)o-xe2x80x9cHeterocyclexe2x80x9d or -(alkyl)oxe2x80x94CO2-(alkyl)u-xe2x80x9cHeterocyclexe2x80x9d,
wherein
o and u independently of each another is 0 or 1, and
xe2x80x9cHeterocyclexe2x80x9d represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxy-alkyl, alkoxy-alkyl, carboxyl, and acyl, and a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-aralkyl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p-CO2-aryl, -(alkyl)p-CO2-aralkyl, -(alkyl)p-xe2x80x9cHeterocyclexe2x80x9d, -(alkyl)p-CO2-xe2x80x9cHeterocyclexe2x80x9d or -(alkyl-CO2)s-(alkyl)t-COR5,
in which formulas
p, s and t independently of each another is 0 or 1,
xe2x80x9cHeterocyclexe2x80x9d represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl,
R5 represents hydrogen, hydroxy, alkyl, alkoxy, hydroxy-alkyl, hydroxy-alkoxy, alkoxy-alkyl, alkoxyxe2x80x94alkoxy, thioalkoxy-alkyl, thioalkoxy-alkoxy, or a group of the formula xe2x80x94NR6R7 or xe2x80x94O-alkyl-NR6R7,
in which formulas
R6 and R7 independently of each another represent hydrogen, alkyl, cycloalkyl or a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl, or
R6 and R7 together with the nitrogen to which they are attached form a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl; or
Rxe2x80x3 represents -(alkyl)m,-CO2R8,
wherein
m is 0 or 1, and
R8 represents hydrogen, alkyl, hydroxy-alkyl, alkoxy-alkyl, thioalkoxy-alkyl, or a group of the formula -(alkyl)p-NR9R10,
wherein
p is 0 or 1 and
R9 and R10 independently of each another represent hydrogen, alkyl, cycloalkyl, or a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl, or
R9 and R10 together with the nitrogen to which they are attached form a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alky), alkoxy-alkyl, carboxyl and acyl.
In its second aspect, the invention provides a pharmaceutical composition containing a therapeutically effective amount of a benzimidazole derivative according to the invention, or a pharmaceutically acceptable addition salt thereof, together with at least one pharmaceutically acceptable carrier, excipient or diluent.
In its third aspect, the invention provides a use of a benzimidazole derivative according to the invention for the manufacture of a medicament for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition is responsive to modulation of the GABA receptor complex.
In its fourth aspect, the invention provides a method for treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to modulation of the GABA receptor complex, which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of a benzimidazole derivative according to the invention.
Other objects of the invention will be apparent to the person skilled in the art from the following detailed description and the working examples.
Benzimidazole Derivatives
In its first aspect the invention provides novel benzimidazole derivatives. The benzimidazole derivatives of the invention are represented by the general Formula I, 
or a pharmaceutically acceptable salt thereof,
wherein,
Rxe2x80x2 represents a group of the formula -(alk)q-R1,
wherein
(alk) represents alkyl, alkenyl or alkynyl,
q is 0 or 1,
R1 represents a group of the formula xe2x80x94CO2R2, wherein
R2 represents hydrogen, alkyl, hydroxy-alkyl, alkoxy-alkyl, thioalkoxy-alkyl, alkyl-xe2x80x9cHeterocyclexe2x80x9d, or -alkyl-NR3R4,
wherein
xe2x80x9cHeterocyclexe2x80x9d represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl, and a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-xe2x80x9cHeterocyclexe2x80x9d, -(alkyl)p-CO2-xe2x80x9cHeterocyclexe2x80x9d or -(alkyl-CO2)s-(alkyl)t-COR5,
in which formulas
p, S and t independently of each another is 0 or 1,
xe2x80x9cHeterocyclexe2x80x9d represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl,
R5 represents hydroxy, alkoxy, hydroxy-alkoxy, alkoxyxe2x80x94alkoxy, thioalkoxy-alkoxy, or a group of the formula xe2x80x94NR6R7 or xe2x80x94O-alkyl-NR6R7,
in which formulas
R6 and R7 independently of each another represent hydrogen, alkyl, cycloalkyl or a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl, or
R6 and R7 together with the nitrogen to which they are attached form a mono- or polycyclic heterocyclic group, which heterocyclic group may be substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl; and
R3 and R4 independently of each another represent hydrogen, alkyl or cycloalkyl, or
R3 and R4 together with the nitrogen to which they are attached form a mono- or poly-cyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl; or
R1 represents a group of the formula 
X represents N or CH,
R12 represents hydrogen, alkyl, alkoxy or hydroxy-alkyl, and
R13 represents hydrogen, hydroxy, alkyl, alkoxy or hydroxy-alkyl; or
R1 represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of alkyl, hydroxy-alkyl, alkoxy-alkyl, carboxyl, and acyl, and a group of the formula -(alkyl)p-aryl, -(alkyl)p-xe2x80x9cHeterocyclexe2x80x9d, -(alkyl)p-CN or -(alkyl-CO2)s-(alkyl)t-COR,
in which formulas
p, s and t independently of each another is 0 or 1,
xe2x80x9cHeterocyclexe2x80x9d represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl,
R5 represents hydroxy, alkoxy, hydroxy-alkoxy, alkoxyxe2x80x94alkoxy, thioalkoxy-alkoxy, or a group of the formula xe2x80x94NR6R7 or xe2x80x94O-alkyl-NR6R7,
in which formulas
R6 and R7 independently of each another represent hydrogen, alkyl, cycloalkyl or a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl, or
R6 and R7 together with the nitrogen to which they are attached form a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl; and
Rxe2x80x3 represents -(alkyl)o-xe2x80x9cHeterocyclexe2x80x9d or -(alkyl)o-CO2-(alkyl)u-xe2x80x9cHeterocyclexe2x80x9d,
wherein
o and u independently of each another is 0 or 1, and
xe2x80x9cHeterocyclexe2x80x9d represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxy-alkyl, alkoxy-alkyl, carboxyl, and acyl, and a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-aralkyl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p-CO2-aryl, -(alkyl)p-CO2-aralkyl, -(alkyl)p-xe2x80x9cHeterocyclexe2x80x9d, -(alkyl)p-CO2-xe2x80x9cHeterocyclexe2x80x9d or -(alkyl-CO2)s-(alkyl)t-COR5,
in which formulas
p, s and t independently of each another is 0 or 1,
xe2x80x9cHeterocyclexe2x80x9d represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl,
R5 represents hydrogen, hydroxy, alkyl, alkoxy, hydroxy-alkyl, hydroxy-alkoxy, alkoxy-alkyl, alkoxyxe2x80x94alkoxy, thioalkoxy-alkyl, thioalkoxy-alkoxy, or a group of the formula xe2x80x94NR6R7 or xe2x80x94O-alkyl-NR6R7,
in which formulas
R6 and R7 independently of each another represent hydrogen, alkyl, cycloalkyl or a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl, or
R6 and R7 together with the nitrogen to which they are attached form a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl; or
Rxe2x80x3 represents -(alkyl)m-CO2R8,
wherein
m is 0 or 1, and
R8 represents hydrogen, alkyl, hydroxy-alkyl, alkoxy-alkyl, thioalkoxy-alkyl, or a group of the formula -(alkyl)p-NR9R10,
wherein
p is 0 or 1, and
R9 and R10 independently of each another represent hydrogen, alkyl, cycloalkyl, or a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl, or
R9 and R10 together with the nitrogen to which they are attached form a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl.
In a preferred embodiment the benzimidazole derivative of the invention is represented by Formula I, wherein Rxe2x80x3 represents
2-(4-acetylpiperazin-1-yl)-ethoxy-carbonyl;
pyridin-2-y,-methoxy-carbonyl;
1-Methyl-2-pyrrolidyl-methoxy-carbonyl; or
3,5-dimethyl-1-piperazinyl-ethoxy-carbonyl.
In a most preferred embodiment, the benzimidazole derivative is
2-(1-Acetyl-4-piperazinyl)-ethyl 3-(5-(3-furanyl)-1-benzimidazoyl)-benzoate;
1-Methyl-2-pyrrolidylmethyl 3-(5-(3-furanyl)-1-benzimidazolyl)-benzoate;
or a pharmaceutically acceptable salt thereof.
In another preferred embodiment the benzimidazole derivative of the invention is a compound of Formula I, wherein
R1 represents a group of the formula xe2x80x94CO2R2, wherein
R2 represents alkyl, hydroxy-alkyl, alkoxy-alkyl, thioalkoxy-alkyl, alkyl-N(alkyl)2; or
R1 represents a group of the formula 
R12 represents alkyl, and
R13 represents hydroxy, or alkoxy; or
R1 represents a furanyl group, a pyrazolyl group, an isoxazolyl group, an oxazolyl group, an oxadiazolyl group.
In a more preferred embodiment
R1 represents a group of the formula xe2x80x94COOH, xe2x80x94CO2xe2x80x94CH3, xe2x80x94CO2xe2x80x94C2H5, xe2x80x94CO2xe2x80x94CH2xe2x80x94CH(OH), xe2x80x94CO2(CH2)2OCH3, xe2x80x94CO2(CH2)2SCH3, xe2x80x94CO2(CH2)2SC2H5, or xe2x80x94CO2(CH2)2N(CH3)2; or
R1 represents a group of the formula 
R12 represents methyl or ethyl, and
R13 represents hydroxy, methoxy or ethoxy; or
R1 represents a 2- or 3-furanyl group.
In a most preferred embodiment, the benzimidazole derivative is
2-(3,5-dimethyl-1-piperazinyl)-ethyl 3-(5-acetylbenzimidazol-1-yl)-benzoate oxime; or
2-(2-pyridyl)-methyl 3-(5-acetylbenzimidazol-1-yl)-benzoate oxime;
or a pharmaceutically acceptable salt thereof.
In another preferred embodiment the benzimidazole derivative of the invention is represented by Formula 1, wherein
Rxe2x80x3 represents a group of the formula -(alkyl)o-xe2x80x9cHeterocyclexe2x80x9d, wherein
o is 0 or 1, and
xe2x80x9cHeterocyclexe2x80x9d represents a furanyl group, a 2H-furanyl group, a 4H-furanyl group, a thienyl group, a pyrrolyl group, a 2H-pyrrolyl (pyrrolinyl) group, a 4H-pyrrolyl (pyrrolidinyl) group, an imidazolyl group, an oxazolyl group, a 2H-oxazolyl (oxazolinyl) group, a 4H-oxazolyl (oxazolidinyl) group, an isoxazolyl group, a 2H-isoxazolyl (isoxazolinyl) group, a 4H-isoxazolyl (isoxazolidinyl) group, an oxadiazolyl group, a 2H-oxadiazolyl (oxadiazolinyl) group, a 4H-oxadiazolyl (oxadiazolidinyl) group, a morpholinyl group, a thiomorpholinyl group, a pyridinyl group, a piperidinyl group, a piperazine group, a homopiperazine group or a tetrazolyl group, which heterocyclic groups may be substituted one or more times with substituents selected from the group consisting of halogen, alkyl, oxo, acyl, alkyl-CO2H, alkyl-CO2-alkyl-(alkyl)p-CO2-aryl, -(alkyl)p-CO2-aralkyl and alkyl-CO2-alkyl-CONR6R7 wherein
R6 and R7 independently of each another represent hydrogen or alkyl.
In a more preferred embodiment,
xe2x80x9cHeterocyclexe2x80x9d represents a pyrrolidin-1-yl; a piperazin-1-yl; a homopiperazin-1-yl; an imidazol-1-yl; a pyridin-4-yl; a 4H-pyridin-4-yl, in particular a 1,2,5,6-tetrahydro-pyridin-4-yl; a piperidin-4-yl; a 2H-isoxazol-3-yl, in particular a 4,5-dihydro-isoxazol-3-yl.
In a further preferred embodiment the benzimidazole derivative of the invention is represented by Formula I, wherein Rxe2x80x3
4-ethoxycarbonyl-1-imidazolyl;
4-methoxycarbonyl-1-imidazolyl;
5-((N, N-Diethylcarbamoyl)-methoxy-carbonyl-methyl)4, 5-dihydroisoxazol-3-yl;
5-((N,N-Dimethylcarbamoyl)-methoxy-carbonyl-methyl)-4,5-dihydroisoxazol-3-yl;
1-imidazolylmethyl;
4-(1-methyl-5-tetrazolyl)-methyl-1-piperazinyl;
1-ethyl-1,2,5,6-tetrahydropyridin-4-yl;
4-(2-oxazolidinone-5-yl)-methyl)1-piperazinyl;
4-(5-methyloxadiazol-3-yl)-methyl)1-piperazinyl;
4-(3,5-dimethylisoxazol-4-yl)-methyl)1-piperazinyl;
4-(2-oxo-tetrahydrofuran-3-yl)-1-piperazinyl;
4-(2-chloro-5-thienyl)-methyl-1-piperazinyl; or
(1-methyl-2-pyrrolidyl)-methyl-carbonyl.
In a most preferred embodiment the benzimidazole derivative of the invention is
2-Methoxyethyl 1-(3-(4-methoxycarbonyl-1-imidazolyl)-phenyl)-benzimidazole-5-carboxylate;
(N,N-Diethylcarbamoyl)-methyl 2-(3-[3-(5-ethoxycarbonyl-1-benzimidazolyl)-phenyl]-4,5-dihydroxyisoxazol-5-yl)-acetate;
Methyl 1-(3-(1-imidazolylmethyl)-phenyl)-benzimidazole-5-carboxylate;
2-(Methylthio)-ethyl 1-(3-(1-imidazolylmethyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-(1-methyl-5-tetrazolyl)methyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(1-ethyl-1,2,5,6-tetrahydropyridin-4-yl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-(2-oxazolidinone-5-yl)-methyl)1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-(5-methyloxadiazol-3-yl)-methyl)1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-(3,5-dimethylisoxazol-4-yl)methyl) 1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-(2-oxo-tetrahydrofuran-3-yl)-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-(2-chloro-5-thienyl)-methyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
5-(3-Furanyl)-1-(3-(4-methoxycarbonyl-1-imidazolyl)-phenyl)-benzimidazole; or
N,N-Diethylcarbamoylmethyl 2-(3-(3-(5-(3-furanyl)-1-benzimidazolyl)-phenyl)-4,5-dihydroisoxazole-5-yl)-acetate;
or a pharmaceutically acceptable salt thereof.
In another preferred embodiment the benzimidazole derivative of the invention is represented by Formula I wherein
Rxe2x80x3 represents a group of the formula xe2x80x94CO2-(alkyl)o-xe2x80x9cHeterocyclexe2x80x9d, wherein o is 0 or 1,and
xe2x80x9cHeterocyclexe2x80x9d represents a pyrrolyl group, a 2H-pyrrolyl (pyrrolinyl) group, a 4H-pyrrolyl (pyrrolidinyl) group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a 2H-isoxazolyl (isoxazolinyl) group, a 4H-isoxazolyl (isoxazolidinyl) group, an oxadiazolyl group, a pyridyl group, a piperidinyl group, a piperazine group or a homopiperazine group, which heterocyclic groups may be substituted one or more times with substituents selected from the group consisting of alkyl, acyl, alkyl-CO2H, alkyl-CO2-alkyl and alkyl-CO2-alkyl-CONR6R7, wherein
R6 and R7 independently of each another represent hydrogen or alkyl.
In a more preferred embodiment the benzimidazole derivative of the invention is represented by Formula I, wherein
Rxe2x80x3 represents a group of the formula 
in which formula
o is 0 or 1,
n is 0, 1 or 2,
X represents N or CH,
Y represents O, NR1 or CHR11,
wherein R11 represents hydrogen, alkyl, hydroxy-alkyl, alkoxy-alkyl, carboxyl or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p-xe2x80x9cHeterocyclexe2x80x9d, -(alkyl)p-CO2-xe2x80x9cHeterocyclexe2x80x9d or -(alkyl-CO2)s-(alkyl)t-COR5,
wherein
p, s and t independently of each another is 0 or 1,
xe2x80x9cHeterocyclexe2x80x9d represents a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxy-alkyl, alkoxy-alkyl, carboxyl and acyl,
R5 represents hydroxy, alkoxy, hydroxy-alkoxy, alkoxyxe2x80x94alkoxy, thioalkoxy-alkoxy, aryl or aralkyl, or a group of the formula xe2x80x94NR6R7 or xe2x80x94O-alkyl-NR6R7, in which formulas
R6 and R7 independently of each another represents hydrogen, alkyl, cycloalkyl or a mono- or polycyclic heterocyclic group, which heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of alkyl, and acyl, or
R6 and R7 together with the nitrogen to which they are attached form a mono- or polycyclic heterocyclic group, which heterocyclic group may be substituted one or more times with substituents selected from the group consisting of alkyl and acyl, and
R14 and R15 independently of each another represent hydrogen, alkyl, hydroxy-alkyl, alkoxy-alkyl, carboxyl or acyl; or
Rxe2x80x3 represents a group of the formula xe2x80x94CO2R8, wherein
R8 represents alkyl-NR9R10, wherein
R9 and R10 together with the nitrogen to which they are attached form a pyrrolidine or a piperazine group, which group may be substituted one or more times with substituents selected from the group consisting of alkyl and acyl.
In an even more preferred embodiment the benzimidazole derivative of the invention is represented by Formula I, wherein Rxe2x80x3 represents
4-methoxycarbonyl-methyl-3,5-dimethyl-1-piperazinyl;
4-ethoxycarbonyl-methyl-3,5-dimethyl-1-piperazinyl;
4-methyl-3,5-dimethyl-1-piperazinyl;
4-ethyl-3,5-dimethyl-1-piperazinyl; or
3,5-dimethyl-1-piperazinyl.
In a most preferred embodiment the benzimidazole derivative of the invention is
2-Methoxyethyl 1-(3-(4-ethoxycarbonylmethyl-3,5-dimethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methyl 1-(3-(4-ethoxycarbonylmethyl-3,5-dimethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-ethyl-3,5-dimethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(3,5-dimethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate; or
2-(3,5-dimethyl-1-piperazinyl)-ethyl 3-(5-acetylbenzimidazol-1-yl)-benzoate oxime;
or a pharmaceutically acceptable salt thereof.
In yet another preferred embodiment the benzimidazole derivative of the invention is represented by Formula I wherein
Rxe2x80x3 represents a group of the formula 
in which formula
o is 0 or 1,
n is 0, 1 or 2,
X represents N or CH, and
Y represents NR11 or CHR11, wherein
R11 represents hydrogen, alkyl, hydroxy-alkyl, carboxy, acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)t-COR5 or (alkyl)t-R5,
wherein
p and t independently of each another is 0 or 1, and
R5 represents hydroxy, alkoxy, NH2, NH(alkyl) or N(alkyl)2.
In a more preferred embodiment,
Rxe2x80x3 represents
4-(methoxy-carbonyl)-1-piperazinylmethyl;
4-(ethoxy-carbonyl)-1-piperazinylmethyl;
4-(methoxy-carbonyl-methyl)-1-piperazinyl;
4-(ethoxy-carbonyl-methyl)-1-piperazinyl;
4-(methoxy-carbonyl-methyl)-1-piperazinylmethyl;
4-(ethoxy-carbonyl-methyl)-1-piperazinylmethyl;
1-piperazinyl;
1-piperazinyl-methyl;
4-acetyl-1-piperazinyl;
4-methyl-1-piperazinyl;
4-ethyl-1-piperazinyl;
4-methyl-4-piperidinyl;
1-acetyl-4-piperidinyl;
1-methyl-4-piperidyl;
1-acetyl-4-piperidyl;
4-tert-butoxycarbonylmethyl-1-piperazinyl;
4-isopropoxycarbonylmethyl-1-piperazinyl;
4-carboxymethyl-1-piperazinyl;
4-benzyl-1-piperazinyl;
4-cyanomethyl-1-piperazinyl;
4-benzyloxy-ethyl-1-piperazinyl;
4-ethyl-1-homopiperazinyl;
4-(2-hydroxy-ethyl)-1-piperazinyl;
4-carbamoylmethyl-1-piperazinyl;
4-dimethylcarbamoylmethyl-1-piperazinyl; or
4-diethylcarbamoylmethyl-1-piperazinyl.
In a most preferred embodiment, the benzimidazole derivative of the invention is
2-Methoxyethyl 1-(3-(4-(ethoxy-carbonyl)-1-piperazinylmethyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-(ethoxy-carbonyl-methyl)-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-carboxymethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-methyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-acetyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(1-methyl-4-piperidyl)phenyl)benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(1-acetyl-4-piperidyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-t-butoxycarbonylmethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-i-propoxycarbonylmethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-[4-(3-(5-Methoxycarbonylbenzimidazol-1-yl)-phenyl)-1-piperazinyl]-acetic acid;
2-(Methylthio)-ethyl 1-(3-(4-methyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-(N,N-dimethylamino)-ethyl 1-(3-(1-carboxymethyl-4-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-benzyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
Methyl 1-(3-(4-cyanomethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-cyanomethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
Methyl 1-(3-(4-benzyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-benzyloxyethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-ethyl-1-homopiperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methyl 1-(3-(4-ethyl-1-homopiperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-ethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Hydroxyethyl 1-(3-(4-(2-hydroxyethyl)-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
Methyl 1-(3-(1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Hydroxyethyl 1-(3-(4-methyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Hydroxyethyl 1-(3-(4-methoxycarbonylmethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Hydroxyethyl 1-(3-(4-ethoxycarbonylmethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-diethylcarbamoylmethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-methoxycarbonylmethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Methoxyethyl 1-(3-(4-carbamoylmethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Hydroxyethyl 1-(3-(4-carbamoylmethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Hydroxyethyl 1-(3-(4-diethylcarbamoylmethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
2-Hydroxyethyl 1-(3-(4-carboxymethyl-1-piperazinyl)-phenyl)-benzimidazole-5-carboxylate;
5-(3-Furanyl)-1-(3-((4-ethoxycarbonyl-1-piperazinyl)-methyl)-phenyl)-benzimidazole;
5-(3-Furanyl)-1-(3-(1-(ethoxy-carbonyl-methyl)4-piperazinyl)-phenyl)-benzimidazole;
5-(3-Furanyl)-1-(3-(4-t-butoxycarbonylmethyl-1-piperazinyl)-phenyl)-benzimidazole;
5-(3-Furanyl)-1-(3-(1-ethoxycarbonylmethyl-4-piperazinylmethyl)-phenyl)-benzimidazole;
5-(3-Furanyl)-1-(3-(1-ethoxycarbonylmethyl-4-piperidyl)-phenyl)-benzimidazole;
5-(3-Furanyl)-1-(3-(4-ethoxycarbonylpiperid-1-ylmethyl)-phenyl)-benzimidazole; or
5-(3-Furanyl)-1-(3-(1-ethoxycarbonyl-4-piperazinyl)-phenyl)-benzimidazole;
or a pharmaceutically acceptable salt thereof.
Definition of Substituents
In the context of this invention halogen represents a fluorine, a chlorine, a bromine or an iodine atom.
In the context of this invention an alkyl group designates a univalent saturated, straight or branched hydrocarbon chain. The hydrocarbon chain preferably consists of from one to eight carbon atoms (C1-8-alkyl), more preferred from one to six carbon atoms (C1-6-alkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl. In a preferred embodiment alkyl represents a C1-4-alkyl group, including butyl, isobutyl, secondary butyl, and tertiary butyl. In a preferred embodiment of this invention alkyl represents a C1-3-alkyl group, which may in particular be methyl, ethyl, propyl or isopropyl.
In the context of this invention a cycloalkyl group designates a cyclic alkyl group, preferably containing of from three to seven carbon atoms (C3-7-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
In the context of this invention an alkenyl group designates a carbon chain containing one or more double bonds, including di-enes, tri-enes and poly-enes. In a preferred embodiment the alkenyl group of the invention comprises of from two to six carbon atoms (C2-6-alkenyl), including at least one double bond. In a most preferred embodiment the alkenyl group of the invention is ethenyl; 1,2- or 2,3-propenyl; or 1,2-, 2,3-, or 3,4-butenyl.
In the context of this invention an alkynyl group designates a carbon chain containing one or more triple bonds, including di-ynes, tri-ynes and poly-ynes. In a preferred embodiment the alkynyl group of the invention comprises of from two to six carbon atoms (C2-6-alkynyl), including at least one triple bond. In its most preferred embodiment the alkynyl group of the invention is ethynyl, 1,2- or 2,3-propynyl, 1,2-, 2,3- or 3,4-butynyl.
In the context of this invention an alkoxy-alkyl group designates an xe2x80x9calkyl-O-alkyl-xe2x80x9d group, wherein alkyl is as defined above.
In the context of this invention a thioalkoxy-alkyl group designates an xe2x80x9calkyl-S-alkylxe2x80x9d group wherein alkyl is as defined above;
In the context of this invention an alkoxyalkoxy group designates O-alkyl-O-alkyl wherein alkyl is as defined above.
In the context of this invention an thioalkoxy-alkoxy group designates O-alkyl-S-alkyl wherein alkyl is as defined above.
In the context of this invention an acyl group designates a carboxy group (HOOCxe2x80x94), an alkyl-carbonyl group (alkyl-COxe2x80x94), or a cycloalkyl-carbonyl (cycloalkyl-COxe2x80x94), wherein alkyl and cycloalkyl are as defined above. Examples of preferred acyl groups of the invention include carboxy, acetyl, and propionyl.
In the context of this invention an aryl group designates a monocyclic or polycyclic aromatic hydrocarbon group. Examples of preferred aryl groups of the invention include phenyl, naphthyl and anthracenyl.
In the context of this invention an aralkyl group designates a mono- or polycyclic aryl group as defined above, which aryl group is attached to an alkyl group as also defined above. Examples of preferred aralkyl groups of the invention include benzyl, and phenethyl.
In the context of this invention a xe2x80x9cHeterocyclexe2x80x9d designates a mono- or polycyclic heterocyclic group, which is a mono- or polycyclic group, and which group holds one or more heteroatoms in its ring structure. Preferred heteroatoms include nitrogen (N), oxygen (O), and sulphur (S). One or more of the ring structures may in particular be aromatic (i.e. a heteroaryl), saturated or partially saturated. Preferred heterocyclic monocyclic groups of the invention include 5- and 6-membered heterocyclic monocyclic groups. Preferred poly-heterocyclic groups of the invention are the bicyclic heterocyclic groups.
Examples of preferred aromatic heterocyclic 5-membered monocyclic groups of the invention include
furan, in particular 2- or 3-furanyl;
thiophene, in particular 2- or 3-thienyl,
pyrrole (azole), in particular 1-, 2- or 3-pyrrolyl;
oxazole, in particular oxazol-(2-,4- or 5-)yl;
thiazole, in particular thiazol-(2-,4-, or 5-)yl;
imidazole, in particular imidazol-(1-,2-,4- or 5-)yl;
pyrazole, in particular pyrazol-(1-,3-,4- or 5-)yl;
isoxazole, in particular isoxazol-(3-,4- or 5-)yl;
isothiazole, in particular isothiazol-(3-,4- or 5-)yl;
1,2,3-oxadiazole, in particular 1,2,3-oxadiazol-(4- or 5-)yl;
1,2,4-oxadiazole, in particular 1,2,4-oxadiazol-(3- or 5-)yl;
1,2,5-oxadiazole, in particular 1,2,5-oxadiazol-(3- or 4-)yl;
1,2,3-triazole, in particular 1,2,3-triazol-(1-,4- or 5-)yl;
1,2,4-thiadiazole, in particular 1,2,4-thiadiazol-(3- or 5-)yl;
1,2,5-thiadiazole, in particular 1,2,5-thiadiazol-(3- or 4-)yl; and
1,3,4-thiadiazole, in particular 1,3,4-thiadiazol-(2- or 5-)yl.
Examples of preferred saturated or partially saturated heterocyclic monocyclic 5-membered groups of the invention include
1,3-dioxolan, in particular 1,3-dioxolan-(2- or 4-)yl;
imidazolidine, in particular imidazolidin-(1-,2-,3-,4- or 5-)yl;
2-imidazoline, in particular 2-imidazolin-(1-,2-,4- or 5-)yl;
3-imidazoline, in particular 3-imidazolin-(1-,2-,4- or 5-)yl;
4-imidazoline, in particular 4-imidazolin-(1-,2-,4- or 5-)yl;
2H-oxazole (oxazoline), in particular 2H-oxazol-(2-,4- or 5-)yl;
4H-oxazole (oxazolidine), in particular 4H-oxazol-(2-,4- or 5-)yl;
1,2,3-oxadiazoline, in particular 1,2,3-oxadiazol-(4- or 5-)yl;
1,2,4-oxadiazoline, in particular 1,2,4-oxadiazol-(3- or 5-)yl;
1,2,5-oxadiazoline, in particular 1,2,5-oxadiazol-(3- or 4-)yl;
1,2,3-oxadiazolidine, in particular 1,2,3-oxadiazol-(4- or 5-)yl;
1,2,4-oxadiazolidine, in particular 1,2,4-oxadiazol-(3- or 5-)yl;
1,2,5-oxadiazolidine, in particular 1,2,5-oxadiazol-(3- or 4-)yl;
2H-pyrrole (pyrroline), in particular 2H-pyrrol-(1-,2- or 3-)yl;
4H-pyrrole (pyrrolidine), in particular 4H-pyrrol-(1-,2- or 3-)yl;
pyrazolidine, in particular pyrazolidin-(1-,2-,3-,4- or 5-)yl;
2-pyrazoline, in particular 2-pyrazolin-(1-,3-,4- or 5-)yl; and
3-pyrazoline, in particular 3-pyrazolin-(1-,3-,4- or 5-)yl.
Examples of preferred aromatic heterocyclic 6-membered monocyclic groups of the invention include
pyridine, in particular pyridin-(2-,3- or 4-)yl;
pyridazine, in particular pyridazin-(3- or 4-)yl;
pyrimidine, in particular pyrimidin-(2-,4- or 5-)yl;
pyrazine, in particular pyrazin-(2-,3-,5- or 6-)yl;
1,3,5-triazine, in particular 1,3,5-triazin-(2-,4- or 6-)yl; and
phosphinine, in particular phosphinin-(2-,3- or 4-)yl.
Examples of preferred saturated or partially saturated heterocyclic monocyclic 6-membered groups of the invention include
1,4-dioxolane, in particular 1,4-dioxolan-(2- or 3-)yl;
1,4-dithiane, in particular 1,4-dithian-(2- or 3-)yl;
morpholine, in particular morpholin-(2-,3- or 4-)yl;
1,4-oxazane, in particular 1,4-oxazin-(2-)yl;
oxadiazine, in particular oxadiazin-(2-,3- or 5-)yl;
piperidine, in particular piperidin-(1-,2-,3- or 4-)yl;
piperazine, in particular piperazin-(1-,2-,3- or 4-)yl;
2H-pyrane, in particular 2H-pyran-(2-,3- or 4-)yl;
4H-pyrane, in particular 4H-pyran-(2-,3- or 4-)yl;
thiomorpholine, in particular thiomorpholin-(2-,3- or 4-)yl; and
1,3,5-trithiane, in particular 1,3,5-trithian-(2-)yl.
Examples of preferred saturated or partially saturated heterocyclic monocyclic 7-membered groups of the invention include homopiperidine, in particular homopiperidin-(1-,2-,3- or 4-)yl; and
homopiperazine, in particular homopiperazin-(1-,2-,3- or 4-)yl.
Examples of preferred aromatic heterocyclic bi-cyclic groups of the invention include indolizine, in particular indolizin-(1-,2-,3-,5-,6-,7- or 8)yl;
indole, in particular indol-(1-,2-,3-,4-,5-,6- or 7)yl;
isoindole, in particular isoindol-(1-,2-,3-,4-,5-,6- or 7-)yl;
benzo[b]furan (benzofuran), in particular benzo[b]furan-(2-,3-,4-,5-,6- or 7-)yl;
benzo[c]furan (isobenzofuran), in particular benzo[c]furan-(1-,3-,4-,5-,6- or 7-)yl;
benzo[b]thiophene (benzothiophene), in particular benzo[b]thiophen-(2-, 3-,4,5-,6- or 7-)yl;
benzo[c]thiophene (isobenzothiophene), in particular benzo[c]thiophen-(1-,3-,4-,5-,6- or 7-)yl;
benzimidazole, in particular benzimidazol-(1-,2-,4-,5-,6- or 7-)yl;
benzthiazole, in particular benzthiazol-(2-,4-,5-,6- or 7-)yl;
purine, in particular purin-(2-,6- or 8-)yl;
quinoline, in particular quinolin-(2-,3-,4-,5-,6-,7- or 8-)yl;
isoquinoline, in particular isoquinolin-(1-,3-,4-,5-,6-,7- or 8-)yl;
cinnoline, in particular cinnolin-(3-,4-,5-,6-,7- or 8-)yl;
phthlazine, in particular phthlazin-(1-,4-,5-,6-,7- or 8-)yl;
quinazoline, in particular quinazolin-(2-,4-,5-,6-,7- or 8-)yl;
quinoxaline, in particular quinoxalin-(2-,3-,5-,6-,7- or 8-)yl;
1,8-naphthyridine, in particular 1,8-naphthyridin-(2-,3-,4-,5-,6- or 7-)yl; and
pteridine, in particular pteridin-(2-,4-,6- or 7-)yl.
Examples of preferred aromatic heterocyclic tri-cyclic groups of the invention include
carbazole, in particular carbazol-(1-,2-,3-,4-,5-,6-,7-,8- or 9-)yl;
acridine, in particular acridin-(1-,2-,3-,4-,5-,6-,7-,8- or 9-)yl;
phenazine, in particular phenazin-(1-,2-,3-,4-,6-,7-,8- or 9-)yl;
phenothiazine, in particular phenothiazin-(1-,2-,3-,4-,6-,7-,8-,9- or 10-)yl; and
phenoxazine, in particular phenoxazin-(1-,2-,3-,4-,6-,7-,8-,9- or 10-)yl.
Examples of preferred saturated or partially saturated heterocyclic bi-cyclic groups of the invention include
indoline, in particular indolin-(1-,2-,3-,4-,5-,6- or 7-)yl;
3H-indole, in particular 3H-indol-(2-,3-,4-,5-,6- or 7-)yl;
1H-indazole, in particular 1H-indazol-(3-,4-,5-,6- or 7-)yl;
4H-quinolizine, in particular 4H-quinolizin-(1-,2-,3-,4-6-,7-,8- or 9-)yl;
quinuclidine, in particular quinuclidin-(2-,3-,4-,5-,6-,7- or 8-)yl;
isoquinuclidine, in particular isoquinuclidin-(1-,2-,3-,4-,5-,6-,7- or 8-)yl;
tropane, in particular tropan-(i-,2-,3-,4-,5-,6-,7- or 8-)yl; and
nortropane, in particular nortropan-(I-,2-,3-,4-,5-,6- or 7-)yl.
Pharmaceutically Acceptable Salts
The chemical compound of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre- or prodrug forms of the chemical compound of the invention.
Examples of pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride derived from hydrochloric acid, the hydrobromide derived from hydrobromic acid, the nitrate derived from nitric acid, the perchlorate derived from perchloric acid, the phosphate derived from phosphoric acid, the sulphate derived from sulphuric acid, the formate derived from formic acid, the acetate derived from acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesulphonate derived from benzensulphonic acid, the benzoate derived from benzoic acid, the cinnamate derived from cinnamic acid, the citrate derived from citric acid, the embonate derived from embonic acid, the enantate derived from enanthic acid, the fumarate derived from fumaric acid, the glutamate derived from glutamic acid, the glycolate derived from glycolic acid, the lactate derived from lactic acid, the maleate derived from maleic acid, the malonate derived from malonic acid, the mandelate derived from mandelic acid, the methanesulphonate derived from methane sulphonic acid, the naphthalene-2-sulphonate derived from naphtalene-2-sulphonic acid, the phthalate derived from phthalic acid, the salicylate derived from salicylic acid, the sorbate derived from sorbic acid, the stearate derived from stearic acid, the succinate derived from succinic acid, the tartrate derived from tartaric acid, the toluene-p-sulphonate derived from p-toluene sulphonic acid, and the like. Such salts may be formed by procedures well known and described in the art.
Other acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt.
Metal salts of a chemical compound of the invention includes alkali metal salts, such as the sodium salt of a chemical compound of the invention containing a carboxy group.
In the context of this invention the xe2x80x9conium saltsxe2x80x9d of N-containing compounds are also contemplated as pharmaceutically acceptable salts. Preferred xe2x80x9conium saltsxe2x80x9d include the alkyl-onium salts, the cycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.
The chemical compound of the invention may be provided in dissoluble or indissoluble forms together with a pharmaceutically acceptable solvents such as water, ethanol, and the like. Dissoluble forms may also include hydrated forms such as the monohydrate, the dihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and the like. In general, the dissoluble forms are considered equivalent to indissoluble forms for the purposes of this invention.
Steric Isomers
The chemical compounds of the present invention may exist in (+) and(xe2x88x92) forms as well as in racemic forms. The racemates of these isomers and the individual isomers themselves are within the scope of the present invention.
Racemic forms can be resolved into the optical antipodes by known methods and techniques. One way of separating the diastereomeric salts is by use of an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optical active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallisation of d- or I-(tartrates, mandelates, or camphorsulphonate) salts for example.
The chemical compounds of the present invention may also be resolved by the formation of diastereomeric amides by reaction of the chemical compounds of the present invention with an optically active activated carboxylic acid such as that derived from (+)or (xe2x88x92)phenylalanine, (+)or (xe2x88x92)phenylglycine, (+)or (xe2x88x92)camphanic acid or by the formation of diastereomeric carbamates by reaction of the chemical compound of the present invention with an optically active chloroformate or the like.
Additional methods for the resolving the optical isomers are known in the art. Such methods include those described by Jaques J. Collet A, and Wilen S in xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, New York (1981).
Optical active compounds can also be prepared from optical active starting materials.
Moreover, some of the chemical compounds of the invention may exist in two forms, cis- and trans-form (Z- and E-form), depending on the arrangement of the substituents around the xe2x80x94Cxe2x95x90Cxe2x80x94 double bond. A chemical compound of the present invention may thus be the cis- or the trans-form (Z- and E-form), or it may be a mixture hereof.
Methods of Preparation
The benzimidazole derivatives of the invention may be prepared by conventional methods for chemical synthesis, e.g. those described in the working examples. The starting materials for the processes described in the present application are known or may readily be prepared by conventional methods from commercially available chemicals.
Also one compound of the invention can be converted to another compound of the invention using conventional methods.
The end products of the reactions described herein may be isolated by conventional techniques, e.g. by extraction, crystallisation, distillation, chromatography, etc.
Pharmaceutical Compositions
In another aspect the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the benzimidazole derivative of the invention.
While a chemical compound of the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
In a preferred embodiment, the invention provides pharmaceutical compositions comprising the chemical compound of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers therefor, and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.
Pharmaceutical compositions of the invention may be those suitable for oral, rectal, bronchial, nasal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for administration by inhalation or insufflation, including powders and liquid aerosol administration, or by sustained release systems. Suitable examples of sustained release systems include semi-permeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices may be in form of shaped articles, e.g. films or microcapsules.
The chemical compound of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof. Such forms include solids, and in particular tablets, filled capsules, powder and pellet forms, and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with the same, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
The chemical compound of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a chemical compound of the invention or a pharmaceutically acceptable salt of a chemical compound of the invention.
For preparing pharmaceutical compositions from a chemical compound of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.
In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term xe2x80x9cpreparationxe2x80x9d is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glyceride or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
The chemical compound according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
For topical administration to the epidermis the compound of the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
Compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The compositions may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump.
Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (OFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.
Alternatively the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
When desired, compositions adapted to give sustained release of the active ingredient may be employed.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
Further details on techniques for formulation and administration may be found in the latest edition of Remington""s Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).
A therapeutically effective dose refers to that amount of active ingredient which ameliorates the symptoms or condition. Therapeutic efficacy and toxicity, e.g. ED50 and LD50, may be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index and may be expressed by the ratio LD50/ED50. Pharmaceutical compositions which exhibit large therapeutic indexes are preferred.
The dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage should of course be determined by the practitioner.
The actual dosage depend on the nature and severity of the disease being treated and the route of administration, and is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect. However, it is presently contemplated that pharmaceutical compositions containing of from about 0.1 to about 500 mg of active ingredient per individual dose, preferably of from about 1 to about 100 mg, most preferred of from about 1 to about 10 mg, are suitable for therapeutic treatments.
The active ingredient may be administered in one or several doses per day. A satisfactory result can, in certain instances, be obtained at a dosage as low as 0.1 xcexcg/kg i.v. and 1 xcexcg/kg p.o. The upper limit of the dosage range is presently considered to be about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred ranges are from about 0.1 xcexcg/kg to about 10 mg/kg/day i.v., and from about 1 xcexcg/kg to about 100 mg/kg/day p.o.
As the preferred way of administration is intravenous and by infusion the dose ranges are from 0.01 xcexcg/kg/h to about 10 mg/kg/h.
Biological Activity
It is an object of the present invention to provide compounds capable of modulating the GABAA receptor complex, which object is met by the provision of the novel benzimidazole derivatives of Formula I.
The benzimidazole derivatives of the invention are particularly useful as anaesthetics and/or pre-anaesthetics, for inducing and maintaining anaesthesia, as sedatives, as muscle relaxants, and for combating febrile convulsions in children, status epilepticus, for use to patients constrained to a respirator.
The benzimidazole derivatives of the invention show a short duration of action, they are water soluble at therapeutic relevant doses, and are particular well suited for intravenous administration.
The compounds of the invention may also be used by veterinarians.
As demonstrated in the working examples the benzimidazole derivatives of the invention show high to moderate affinity for the benzodiazepine receptor as measured by displacement at 3H-flunitrazepam in vitro as well as in vivo. The most preferred compounds are full agonists i.e. they exert a high maximal effect in the seizure test as described in the application.
Preferred compounds are full agonists on the GABAA receptor complex, e.g. as measured by the anticonvulsant activity in the ptz-test described in Example 14, and give rise to a 2-5 fold increase of the tolerated ptz dose. The most preferred compounds are those which increase the tolerated dose the most.
The benzimidazole derivatives of the invention show half-lives of below 30 minutes, which allows for a short duration of action. Preferred half-lives are in the range of from about 30 seconds to about 20 minutes. Most preferred half-lives are in the range of from about 2 to about 5 minutes.
The preferred compounds induce a rapid onset of anaesthesia, i.e. in less than 1-2 minutes. Most preferred is an onset of anaesthesia in less than 1 minute.
Awakening from anaesthesia following a bolus injection (i.v.), or following the attenuation of an infusion, should occur within a short period of time, i.e. of from about 5 to about 30 minutes, preferably of from about 5 to about 10 minutes, after which time the patient should normalise rapidly, i.e. in less than 40 minutes, preferably in less than 20 minutes, as measured from awakening.
The compounds of this invention can be used together with analgetic compounds such as Remifentanile, Fentanyl, or other opiods.
Methods of Therapy
In another aspect the invention provides a method for the treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disease, disorder or condition is responsive to modulation of the GABA receptor complex, and which method comprises administering to such a living animal body, including a human, in need thereof an effective amount of benzimidazole derivative of the invention.
In a more preferred embodiment the invention provides a method for the induction or maintenance of anaesthesia or pre-anaesthesia, muscle relaxation or sedation, or for the treatment, prevention or alleviation of fewer cramps or status epilepticus.
It is at present contemplated that suitable infusion rates are in the range of from about 0.01 to about 100 mg/kg/hour, more preferred of from about 0.1 to about 15 mg/kg/hour, dependent upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.